HCA2 activation in Pemphigoid Diseases - therapeutic effect and mode of action

在P8中，我们研究了富马酸二甲酯（DMF）治疗类天疱疮疾病（PDs）的药理学基础。在肠道中，DMF被转化为富马酸单甲基（MMF），一种G蛋白偶联受体HCA2 （GPR109A）的激动剂。事实上，我们在大疱性类天疱疮（BP）样大疱性获得性表皮松解症（EBA）小鼠模型中发现了HCA2介导口服DMF最近描述的保护作用的证据。因此，DMF改善了雌性Hcar2+/+小鼠类天疱疮疾病样皮肤病变，但在Hcar2-/-小鼠中没有。出乎意料的是，经载体处理的雌性Hcar2-/-动物受到EBA的部分保护，这表明HCA2具有双面功能：内源性激动剂激活时有害，外源性药物激活时有益。在第二篇FP中，我们将研究这种矛盾功能的原因，以牢固地确立HCA2作为治疗pd的药物靶点。首先，我们将通过改变饮食来仔细研究内源性HCA2激活剂的作用，包括丁酸盐、β-羟基丁酸盐和烟酸。由于饮食相关代谢物对PD病理的潜在影响可能对患者护理产生重要影响，我们将通过在小鼠和人类患者中进行代谢组学研究来寻找HCA2激活的间接证据。其次，我们将定义介导内源性和药理学HCA2激活剂作用的细胞类型。我们已经生成了一种新的小鼠系，将loxP位点插入到Hcar2基因座中，从而可以对这个问题进行最先进的研究。如果在靶细胞中没有完全重叠，我们的目标是将药理学HCA2激活限制在体隔室，其中有益作用占上风。第三，我们将讨论内源性和药理学HCA2激活剂的动力学特征，这可能解释它们的不同作用。为了接近这一点，我们将确定该药物在BP患者口服给药后的血浆浓度动力学特征，这些患者将是由CRU财团发起并由欧盟委员会资助的BP DMF临床试验的一部分，并将通过皮下植入可调节泵注入该化合物在小鼠身上建立模型。

In P8, we have investigated the pharmacological basis of using dimethyl fumarate (DMF) in the treatment of pemphigoid diseases (PDs). Already in the gut, DMF is converted into monomethyl fumarate (MMF), an agonist of the G protein coupled receptor HCA2 (GPR109A). Indeed, we found evidence that HCA2 mediates the recently described protective effect of oral DMF in a mouse model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA). Thus, DMF ameliorated pemphigoid disease-like skin lesions in female Hcar2+/+ mice, but not in Hcar2-/- animals. Unexpectedly, vehicle-treated female Hcar2-/- animals were partially protected from EBA suggesting a Janus-faced function of HCA2: detrimental if activated by endogenous agonists and beneficial in response to exogenously applied drugs. In the 2nd FP, we will investigate the reason of this ambivalent function to firmly establish HCA2 as a drug target for the treatment of PDs. First, we will scrutinize the role of endogenous HCA2 activators, including butyrate, β-hydroxybutyrate, and nicotinic acid, by modifying the diet. As a potential effect of diet-related metabolites on PD pathology could have important ramifications for patient care, we will search for indirect evidence of HCA2 activation by performing metabolomic studies in mice and human patients. Second, we will define the cell type(s) that mediate effects of endogenous and pharmacological HCA2 activators. A state-of-the-art investigation of this question is possible using a novel mouse line, we have generated, in which loxP sites have been inserted into the Hcar2 locus. If there is no complete overlap in the target cells, we will aim to limit pharmacological HCA2 activation to the body compartment, in which beneficial effects prevail. Third, we will address the kinetic profiles of endogenous and pharmacological HCA2 activators that may explain their distinct actions. To approach this point, we will determine the kinetic profile of the drug’s plasma concentrations after oral administration in BP patients, who will be part of the clinical trial on DMF in BP, initiated by the CRU consortium and funded by the EU commission, and will model it in mice by infusing the compound through a subcutaneously implanted adjustable pump.